Use of an H+, K+ -ATPase inhibitor in the treatment of asthma

ABSTRACT

The invention provides a method for the treatment of polyposis which comprises treating a subject suffering from polyposis with an H + , K + -ATPase inhibitor and, optionally, a glucocorticoid. The invention also relates to a pharmaceutical formulation for simultaneous, separate or sequential administration in the treatment of Widal&#39;s Syndrome and in the treatment of asthma.

FIELD OF THE INVENTION

The present invention provides a new treatment for polyposis usingproton pump inhibitors (PPIs), i.e. H⁺, K⁺-ATPase inhibitors.

BACKGROUND OF THE INVENTION

Polyposis can generally arise in the nose and the gastrointestinaltract. In the nose, polyps are pale bags of tissue that arise in thenasal cavity. Their paleness is generally due to poor blood supply. Itis not known what causes the polyps to be formed but their presence isoften associated with certain medical conditions, for example asthma andaspirin intolerance. Within the general population the incidence ofnasal polyps is low at around only 1% but 13% of asthma sufferers and36% of aspirin intolerant asthmatics suffer from nasal polyposis. Thetriple condition of nasal polyposis, aspirin intolerance and asthma isknown as Widal's Syndrome.

Nasal polyposis is generally treated in two stages. Initially areduction in size of the polyps is achieved either by surgery or by theapplication of a topical intranasal steroid preparation, for examplebetamethasone sodium phosphate. Once a reduction in size has beenobtained then long term maintenance of the reduction is necessary byregular use of an intranasal steroid spray such as beclomethasonedipropionate, budesonide, or fluticasone propionate. When rapidamelioration is required, oral steroids such as prednisolone ordexamethasone or synthetic adrenocorticotrophic hormones are used (see VJ Lund Diagnosis and treatment of nasal polyps Brit Med J 1995, 311,1411-4). There are also proposals that non-steroidal antiinflammatorydrug can be used in the treatment of nasal polyposis (see WO 9703659-A).

DETAILED DESCRIPTION OF THE INVENTION

According to the invention there is provided a method for the treatmentof nasal polyps which method comprises treating a subject suffering fromthe said condition with an H⁺, K⁺-ATPase inhibitor. The inventionfurther provides the use of an H⁺, K⁺-ATPase inhibitor in themanufacture of a medicament for the treatment of nasal polyps.

H⁺, K⁺-ATPase inhibitors are a known class of pharmaceutical agentsgenerally used in therapy for the treatment of gastric acid relateddiseases. Examples of H⁺, K⁺-ATPase inhibitors are for instancecompounds known under the generic names omeprazole, lansoprazole,pantoprazole, rabeprazole and leminoprazole. Some of these compounds arefor instance disclosed in EP-A1-0005129, EP-A1-174726, EP-A1-166287 andGB 2163747.

These pharmaceutical substances are generally known to be useful forinhibiting gastric acid secretion in mammals and man by controllinggastric acid secretion at the final step of the acid secretory pathway.Thus, in a more general sense, they may be used for prevention andtreatment of gastric-acid related diseases in mammals and man, includinge.g. reflux oesophagitis, gastritis, duodenitis, gastric ulcers andduodenal ulcers.

It has now surprisingly been found that H⁺, K⁺-ATPase inhibitors areuseful in the treatment of nasal polyps, particularly where knowntreatments have failed.

The H⁺, K⁺-ATPase inhibitors preferably used in the invention arecompounds of the general formula

wherein Het₁ is

Het₂ is

and X is

wherein N in the benzimidazole moiety of Het₂ means that one of the ringcarbon atoms substituted by R₆-R₉ optionally may be exchanged for anitrogen atom without any substituents;

-   R₁ and R₃ each independently represent hydrogen, alkyl, or alkoxy on    the condition that R₁ and R₃ do not simultaneously represent alkoxy;    and R₂ represents alkyl, alkoxy optionally substituted by fluorine,    alkylthio or alkoxyalkoxy; or one of R₁ and R₃ is halogen and the    other is hydrogen and R₂ is 1-morpholino, 1-piperidino or    dialkylamino;-   R₄ and R₅ are the same or different and selected from hydrogen and    alkyl;-   R₆-R₉ are the same or different and selected from hydrogen halogen,    alkyl, alkoxy, haloalkoxy, alkylcarbonyl, and alkoxycarbonyl;-   R₁₀ is hydrogen or R₁₀ and R₃ together complete a ring containing 6    to 8 carbon atoms; and-   R₁₁ represents hydrogen, halogen or alkyl;-   wherein the compound of formula (I) is optionally in the form of an    pharmaceutically acceptable alkaline salt or in its neutral form or    is a single enantiomer or a racemic mixture thereof;-   wherein each alkyl or alkylenyl moiety has a branched or straight    chain and has 1 to 6, preferably 1 to 4, carbon atoms;-   wherein a halogen atom is preferably a fluorine, chlorine, or    bromine atom, preferably a fluorine or chlorine atom.

Examples of particularly preferred compounds according to formula I foruse in the invention are

The H⁺, K⁺-ATPase inhibitor used in the invention is preferably offormula (Ia): in other words it is preferably omeprazole, or an alkalinesalt of omeprazole, the (−)-enantiomer of omeprazole or an alkaline saltthereof.

The compound of formula (I) when optionally in the form of apharmaceutically acceptable alkaline salt is preferably the Mg²⁺, Ca²⁺,Na⁺ or K⁺ salt, more preferably the Mg²⁺ salt.

The H⁺, K⁺-ATPase inhibitor used in the invention can be administeredorally, rectally or parenterally. While the effect of the inhibitors onthe nasal polyps has been established in patients who have takenomeprazole by the oral route, it is believed that the effect of theinhibitor on the polyps is a systemic effect that is not dependent onwhat mode of administration is used. Accordingly a reduction in size ofthe polyps should be obtainable with other routes of administration.

Commercially available pharmaceutical preparations of H⁺, K⁺-ATPaseinhibitors are suitably used in the invention. Examples of suchpreparations for omeprazole include enteric coated pellets of omeprazolefilled in capsules, or formulated into a multiple unit tabled dosageform; enteric coated tablets of omeprazole or an alkaline salt thereof;and solutions for parenteral administration comprising an alkaline saltof omeprazole.

The dose of the H⁺, K⁺-ATPase inhibitor to be administered will varyaccording to the type of nasal polyps to be treated and the condition ofthe patient. However the dosage for oral, rectal or i.v. administrationis generally in the range of from 1 to 100 mg of H⁺, K⁺-ATPase inhibitorper day. Normally an amount of from 10 to 40 mg per day is used for oraladministration.

The invention may be applied in combination with other treatments knownto ameliorate the other symptoms generally associated with nasal polyps,for example asthma. In other words, the invention can be applied in thetreatment of Widal's Syndrome which consists of the conditions of nasalpolyps, asthma and aspirin intolerance. The invention may also beapplied in the treatment of other inflammatory diseases in the upperrespiratory tract such as acute and chronic rhinosinusitis, allergic andnon-allergic rhinitis, as well as in the lower respiratory tract such asasthma. Therefore according to the invention there is further provided amethod for treating Widal's Syndrome and other respiratory tractinflammatory diseases which method comprises simultaneously, separatelyor sequentially administration to a subject suffering from the syndromeor the diseases a pharmaceutical formulation comprising an H⁺, K⁺-ATPaseinhibitor and a glucocorticoid. According to the invention there is alsoprovided a pharmaceutical formulation for simultaneous, separate orsequential administration to be used in the treatment of Widal'sSyndrome or in the treatment of asthma which formulation comprises anH⁺, K⁺-ATPase inhibitor and a glucocorticoid. The invention furtherprovides the use of an H⁺, K⁺-ATPase inhibitor and a glucocorticoid inthe manufacture of such a pharmaceutical formulation.

Preferred glucocorticoids are topically active anti-inflammatorysteroids. Examples of suitable steroids include budesonide; rofleponide;rofleponide palmitate; ciclesonide; momethasone furoate; fluticasonepropionate; 16α, 17α-butylidenedioxy-6α, 9α-difluoro-11β,21-dihydroxypregna-1,4-diene-3,20-dione; 6α,9α-difluoro-11β-hydroxy-16α,17α-dibutylidenedioxy-17α-methylthio-androsta-4-ene-3-one; S-methyl-16α,17α-butylidenedioxy-6α, 9α-difluoro-11β-hydroxy-3-oxo-androsta-1,4-diene17β-carbothioate; methyl9α-chloro-6α-fluoro-11α-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17α-carboxylate;6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3S-yl) ester; tipredane; fluocinoloneacetonide; flunisolide; flumethasone; dexamethasone; betamethasone;beclomethasone dipropionate; deflazacort; cortivazol; or cortisol and/orhydrocortisol, optionally in their pure isomeric forms (where such formsexist) and in the forms of their pharmaceutically acceptable salts.

The steroids for use in the invention may be applied using conventionaldosing rates, e.g. 40 to 3000 μg per day. Administration may be byinhalation orally or intranasally. The steroids can optionally beadapted to be administered from a dry powder inhaler, a pressurisedmetered dose inhaler, or a nebuliser.

When the steroids are administered from a pressurised inhaler, they arepreferably in micronised form. They are suspended or dissolved in aliquid propellant mixture. The propellants which can be used includechlorofluorocarbons, hydrocarbons or hydrofluoroalkanes. Especiallypreferred propellants are P134a (tetrafluoroethane) and P227(heptafluoropropane) each of which may be used alone or in combination.They are optionally used in combination with other propellants and/orsurfactants and/or other excipients, for example ethanol, surfactants,lubricants, anti-oxidants and stabilising agents.

When the steroids are administered via a nebuliser they may be in theform of a nebulised aqueous suspension or solution, with or without asuitable pH or tonicity adjustment, either as a unit dose or multidosedevice.

The invention is described more in detail with reference to thefollowing examples.

EXAMPLE 1

A 53 year old woman who had had Widal's Syndrome for several years butwho had refused surgical treatment of her polyps suffered mild upperabdominal pain and no improvement in the polyps after treatment bytopical and systemic corticosteroids. However within two weeks of beingprescribed 20 mg of omeprazole per day in addition to 100 μg ofbudesonide (Aqua preparation) per nostril/b.i.d. and 6 mg of deflazacortper day, she experienced a progressive improvement in her nasalrespiratory problem. Eventually she recovered completely from thepolyps.

EXAMPLES 2 To 10

Nine patients, each with the conditions shown in the following Table 1,were treated during a two week period. The treatment consisted of 20 mgof omeprazole, 100 μg of intranasal budesonide and 3 to 15 mg of oraldeflazacort (deflazacort was used in such a small quantity to ensure thepatients' compliance). The results are also shown in Table 1. TABLE 1Example No. Condition Result 2 Widal's Syndrome Temporary benefit 3Widal's Syndrome Positive effect 4 Widal's Syndrome Positive effect 5Nasal Polyposis Long term benefit 6 Nasal Polyposis No benefit 7 NasalPolyposis Positive effect 8 Nasal Polyposis Positive effect 9 NasalPolyposis and aspirin Positive effect intolerance  10 -- Nasal Polyposisand asthma No benefit

Where a positive effect is indicated, this means that the patientexperienced a decrease in rhinorrhoea, a marked improvement in nasalrespiratory ventilation and a reduction in the size of the polyps. Thepatient who experienced a temporary benefit by the treatment suffered arecurrence of the polyposis following the withdrawal of omeprazole anddeflazacort (topical anti-inflammatory steroids, i.e. budesonide, weretaken as required). However after treatment with the same regimen wasresumed, a marked reduction in the size of the polyps was achieved.

The patient of Example 5 who experienced a long term benefit initiallyexperienced no benefit at the end of the initial 2 week treatment periodbut continued with omeprazole and was rewarded with a positive effect atthe end of 2 months.

1-11. (canceled)
 12. A method for the treatment of asthma whichcomprises simultaneously, separately or sequentially administration to asubject suffering from asthma with a pharmaceutical formulationcomprising an H⁺, K⁺-ATPase inhibitor and a glucocorticoid, wherein theH⁺, K⁺-ATPase inhibitor is a compound of the formula

wherein Het₁ is

Het₂ is

and X is

wherein N in the benzimidazole moiety of Het₂ means that one of the ringcarbon atoms substituted by R₆ R₉ optionally ma be exchanged for anitrogen atom without any substituents; R₁ and R₃ each independentlyrepresent hydrogen, alkyl, or on the condition that R₁ and R₃ do notsimultaneously represent alkoxy; and R₂ represents alkyl, alkoxyoptionally substituted by fluorine, alkylthio or alkoxyalkoxy; or one ofR₁ and R₃ is halogen and the other is hydrogen and R₂ is 1-morpholino,1-piperidino or dialkylamino; R₄ and R₅ are the same or different andselected from hydrogen and alkyl; R₆-R₉ are the same or different andselected from hydrogen, halogen, alkyl, alkoxy, haloalkoxy,alkylcarbonyl, and alkoxycarbonyl; R₁₀ is hydrogen or R₁₀ and R₃together complete a ring containing 6 to 8 carbon atoms; and R₁₁represents hydrogen, halogen or alkyl; wherein each alkyl or alkoxymoiety in the preceding substituents has a branched or straight chainand has 1 to 6 carbon atoms.
 13. The method according to claim 12,wherein the glucocorticoid is a topically active anti-inflammatorysteroid. 14-18. (canceled)
 19. The method according to claim 13, whereinthe glucocorticoid is budesonide, beclomethasone dipropionate orfluticasone propionate.
 20. The method according to claim 14, whereinthe compound of formula (I) is in the form of a pharmaceuticallyacceptable alkaline salt or in its neutral form or is a singleenantiomer or a racemate thereof.
 21. The method according to claim 14,wherein the compound of formula (I) is a compound of formula


22. The method according to claim 21, wherein the compound of formula(Ia) is in the neutral form or in the form of a pharmaceuticallyacceptable salt, a single enantiomer or a racemate o the compound. 23.The method according to anyone of claims 12, 13 or 19-22, wherein thecompound is omeprazole, the (−)-enantiomer of omeprazole, an alkalinesalt of omeprazole or an alkaline salt of the (−)-enantiomer ofomeprazole.